Abstract IA46: Molecular and genetic profiling in canine lymphoma unravels targets for the human counterpart

Abstract

Abstract Canine lymphoma represents an excellent cancer model for the human counterpart and is the most widely investigated tumor both in veterinary and comparative oncology. Knowledge of the diagnosis, molecular biology, genetic, and epigenetic has progressively grown in recent years, but prognosis in both B- and T-cell lymphoma remains poor. Several lymphoma subtypes are recognized in canine species and diffuse large B-cell lymphoma (DLBCL) is the most frequent, followed by marginal zone lymphoma (MZL) and a peculiar T-cell malignancy named T-zone lymphoma. DLBCL resembles in many elements the human counterpart, including frequency, molecular abnormalities, and similar therapeutic responses to chemotherapy. However, many other aspects are still scarcely known, and a complete characterization becomes fundamental when including dogs with this lymphoma in clinical trials for new molecules. Indeed, the inability to accurately predict outcome poses several limitations when testing efficacy of new drugs. With NGS advent and the dramatic reduction of costs, researchers in veterinary medicine have started to describe canine lymphoma in a similar fashion to rodent models. The aims of this presentation are to provide an overview of the most significant results in canine lymphoma that have been published in the last decade, focusing on molecular and therapeutic aspects of this tumor. About B-cell lymphoma, transcriptomic studies in canine DLBCL, MZL, and follicular lymphoma (FL) have revealed similarities with the human histotypes. Genes involved in B-cell receptor signaling were found to be enriched both in canine DLBCL and MZL, and several Toll-like receptors were overexpressed, suggesting mechanisms associated with human activated B-cell (ABC)-like subtype DLBCL pathogenesis. The aberrant expression of these genes seems to contribute to enhancing proliferation and protection of canine B cells from apoptosis by stimulating NF-κB activity. The biologic role of NF-kB was tested in dogs with DLBCL using NEMO-binding domain peptide in two clinical trials and the compound resulted in safe blocking of NF-kB activity. Previously, treatment with Ibrutinib was found effective in dogs with B-cell lymphoma. Also, genes coding for proteins involved in MYC signaling and PI3K/AKT/mTOR pathway were found to be overexpressed in both DLBCL and MZL. A peculiar MYC deregulation controlled by LIN28B/Let-7 axis was identified only in DLBCL and LIN28B resulted the most upregulated gene both in vivo and in vitro, revealing an important functional relevance and opening new scenarios for treatment of this tumor in dogs. Within this context, the pan-BET inhibitor OTX015, targeting BRD4, was able to reduce proliferation and expression of MYC-associated genes in vitro. When investigating the cell of origin of canine DLBCL, a study from our group showed a segregation of this lymphoma in two transcriptomic subgroups that were further characterized by distinct methylation profiles and associated with survival. The dogs with inferior survival showed a higher expression of transcripts involved in T-cell and macrophage regulation (CD163, CD96, PD-1, PDL-1, CTLA4, CD8a, CD4). Recently, a study explored the mutation profile of canine B- and T-cell lymphoma in three pure breeds. B-cell lymphomas were categorized based on their mutation profile, and TRAF3, BIRC3, and MAP3K14 were found to be frequently mutated. For TRAF3, a combination of somatic frameshift mutations and truncating SNVs in causing down-expression was identified and germ-line mutations were retrieved in some dogs, possibly indicating that inherited mutations in this gene contribute to genetic predisposition to the tumor. In future, we expect an increasing number of preclinical trials including data from dogs with different lymphoma histotypes, but a detailed pathologic and molecular classification of the tumors is definitively needed to avoid biases related to the heterogeneity of this disease. Inclusion of dogs with lymphoma as part of preclinical testing or in parallel with human trials will be a serious advantage both for human and veterinary medicine. However, limitations, including that dogs are from private owners and toxicities, should always be considered. Citation Format: Luca Aresu. Molecular and genetic profiling in canine lymphoma unravels targets for the human counterpart [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA46.